Pyrrolothiazine and pyrrolothiazephine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action

ABSTRACT

Abstract of the Disclosure 
      A pyrrolesulfonamide derivative, Compound (I), which has strong serotonin-2 receptor antagonistic action and low toxicity and less side effects, and is useful as a therapeutic for circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.

Detailed Description of the Invention TECHNICAL FIELD

This invention relates to novel pyrrolesulfonamide derivatives. Morespecifically, this invention is concerned withpyrrolo[2,3-e][1,2]thiazine derivatives, pyrrolo[3,4-e][1,2]thiazinederivatives, pyrrolo[2,3-f][1,2]thiazepine derivatives andpyrrolo-[3,4-f][1,2]thiazepine derivatives, and salts thereof, saidderivatives and salts having strong serotonin-2 receptor antagonisticaction of excellent selectivity and being useful, for example, for theprevention or treatment of ischemic heart diseases such as anginapectoris, arrhythmia, myocardial infarction, congestive heart failureand post-PTCA restenosis, cerebrovascular disturbances such as cerebralinfarction and cerebral sequelae after subarachnoid hemorrhage,peripheral circulatory disturbances such as arteriosclerosis obliterans,thromboangiitis obliterans and Raynaud disease, and hypertension; theirpreparation processes; and pharmaceuticals containing them as effectiveingredients.

BACKGROUND ART

Serotonin is a compound contained abundantly in platelets, which are ablood component, and in a central nervous system, it acts as aneurotransmitter. In platelets, it is released upon stimulation bythromboxane A₂, ADP, collagen or the like, and synergistically acts onrelease of various platelet aggregation factors through activation ofserotonin-2 receptors in the platelets and vascular smooth muscle cellsand also on vasoconstriction by norepinephrine through α₁ receptors,thereby inducing strong platelet aggregation and vasoconstriction [P. M.Vanhoutte, “Journal of Cardiovascular Pharmacology”, Vol. 17 (Supple.5), S6-S12 (1991)].

Serotonin is also known to potentiate proliferation of vascular smoothmuscle cells [S. Araki et al., “Atherosclerosis”, Vol. 83, pp.29-34(1990). It has been considered that, particularly when endothelial cellsare injured as in arteriosclerosis or myocardial infarction, thevasoconstricting action and thrombus forming action of serotonin areexasperated, thereby reducing or even stopping blood supply tomyocardial, cerebral and peripheral organs [P. Golino et al., “The NewEngland Journal of Medicine”, Vol. 324, No. 10, pp.641-648(1991), Y.Takiguchi et al., “Thrombosis and Haemostasis”, Vol. 68(4),pp.460-463(1992), A. S. Weyrich et al., “American Journal ofPhysiology”, Vol. 263, H349-H358(1992)]. Being attracted by such actionsof serotonin or serotonin-2 receptors, various attempts are now underway to use a serotonin-2 receptor antagonist as a pharmaceutical forischemic diseases of the heart, the brain and peripheral tissues.

Several compounds, led by sarpogrelate, are known to have serotonin-2receptor antagonistic action. They however do not include anythinghaving the pyrrolo[2,3-e][1,2]thiazine skeleton,pyrrolo[3,4-e][1,2]thiazine skeleton, pyrrolo[2,3-f][1,2]thiazepineskeleton or pyrrolo[3,4-f][1,2]thiazepine skeleton. Those known to haveserotonin-2 receptor antagonistic action are accompanied with manyproblems to be improved in potency, toxicity, side effects or the like.On the other hand, medicines which have anti-serotonin action andα₁-blocking action in combination are considered to become extremelyeffective medicines for the treatment and prevention of hypertension andischemic heart diseases, because they have possibility to reduce sideeffects, such as orthostatic hypotension and reflex tachycardia, inducedby antihypertensive action on the basis of the α₁-blocking action andhypertension is a serious risk factor for ischemic heart diseases.

DISCLOSURE OF THE INVENTION

In view of the foregoing circumstances, the present inventors haveproceeded with extensive research toward compounds which have strongserotonin-2 receptor antagonistic action and low toxicity and less sideeffects and are useful for the treatment and prevention of ischemicheart diseases, cerebrovascular disturbances and peripheral circulatorydisturbances. As a result, it has been found that pyrrolesulfonamidesrepresented by the below-described formula (I) meet the aboveconditions. It has also been found that the compounds according to thepresent invention include those also having α₁-blocking action incombination and that such compounds are useful as antihypertensives orthe like having less side effects and are widely usable for thetreatment and prevention of circulatory diseases.

The present invention has been completed based on the above describedfindings. A first object of the present invention is to provide apyrrolesulfonamide derivative or a salt thereof, said pyrrolesulfonamidederivative being represented by the following formula (I):

wherein

the ring P represented by

means a pyrrole ring represented by the following structure:

in which R represents an alkyl group, a cycloalkyl group, acycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;

the dashed line indicates the presence or absence of a bond; and, whenthe bond indicated by the dashed line is present, Z₂ is not present andZ₁ represents a hydrogen atom but, when the bond indicated by the dashedline is absent, Z₁ represents a hydrogen atom and Z₂ represents ahydroxyl group; or Z₁ and Z₂ are combined together to represent anoxygen atom or a group NOR₁ in which R₁ represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group or a substituted or unsubstituted aryl group;

l represents 0 or 1;

A represents a substituted or unsubstituted alkylene group, asubstituted or unsubstituted alkenylene group or a substituted orunsubstituted alkynylene group; and

Y represents a group

in which W represents CH, C═ or a nitrogen atom; and, when W representsCH, m stands for 0 or 1, B represents a carbonyl group, a sulfonylgroup, an alkylene group, an alkenylene group, a group -C(OH)R₂- inwhich R₂ represents a substituted or unsubstituted aryl group, a group-CHR₃- in which R₃ represents a substituted or unsubstituted aryl group,or a substituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, m stands for 1, B represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, m standsfor 0 or 1, and B represents a carbonyl group, a sulfonyl group, analkylene group, an alkenylene group or a group -CHR₅- in which R₅represents a substituted or unsubstituted aryl group; E₁ and E₂ eachindependently represents a hydrogen atom or a lower alkyl group; and Drepresents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted aromatic heterocyclic group.

Another object of the present invention is to provide a preparationprocess of the pyrrolesulfonamide derivative (I) or its salt.

A further object of the present invention is to provide a pharmaceuticalwhich comprises the pyrrole-sulfonamide derivative (I) or itspharmaceutically-acceptable salt as an effective ingredient and isusable for the treatment or the like of circulatory diseases.

BEST MODES FOR CARRYING OUT THE INVENTION

In the pyrrolesulfonamide derivatives (I) of the present invention, thering P represents one of the following pyrrole rings:

wherein R has the same meaning as defined above.

Preferred examples of the group R bonded to the nitrogen atom of thepyrrole ring can include linear or branched alkyl groups having 1-8carbon atoms preferably, such as methyl, ethyl, n-propyl, isopropyl andn-pentyl; cycloalkyl groups having 3-8 carbon atoms, such ascyclopropyl, cyclopentyl and cyclohexyl; cycloalkyl-alkyl groups having4-8 carbon atoms, such as cyclopropylmethyl, cyclohexylmethyl andcyclohexylethyl; and aralkyl groups having 7-22 carbon atoms, such asdiphenylmethyl, benzyl and phenethyl. For example, one or more hydrogenatoms of each of these groups may be substituted by a like number ofhalogen atoms such as fluorine, chlorine and/or bromine atoms, alkylgroups having 1-4 carbon atoms preferably, such as methyl and/or ethyl,and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxyand/or ethoxy. Among these, particularly preferred are methyl and ethyl.

Further, l stands for 0 or 1 in the compound (I) according to thepresent invention. As the combination between the ring P and l,preferred examples can be (A) and 1, (A) and 0, and (B) and 1. Of these,the combinations of (A) and 1 and (A) and 0 are particularly preferred.

On the other hand, preferred examples of the group A in the compound (I)according to the present invention can include linear or branchedalkylene groups having 2-10 carbon atoms, such as ethylene,trimethylene, tetramethylene, pentamethylene and octamethylene; linearor branched alkenylene groups having 4-10 carbon atoms, such as2-butenylene and 3-pentenylene; and linear or branched alkynylene groupshaving 4-10 carbon atoms, such as 2-butynylene and 3-pentynylene. One ormore of the hydrogen atoms of each of these groups may be substituted bya like number of halogen atoms such as fluorine, chlorine and/or bromineatoms. Among the above groups, trimethylene and tetramethylene areparticularly preferred.

Further, preferred examples of the group Z₁ and the group Z₂ in thecompound (I) according to the present invention can include thefollowing combinations: when the bond indicated by the dashed line ispresent, Z₂ is not present and Z₁ represents a hydrogen atom; when thebond indicated by the dashed line is absent, Z₁ represents a hydrogenatom and Z₂ represents a hydroxyl group, or Z₁ and Z₂ are combinedtogether to represent an oxygen atom or the group NOR₁.

Preferred examples of R₁ in the group NOR₁ can include a hydrogen atom;linear or branched alkyl groups having 1-4 carbon atoms preferably, suchas methyl and ethyl; aryl groups having 6-14 carbon atoms, such asphenyl and naphthyl; and aralkyl groups having 7-22 carbon atoms, suchas benzyl and phenethyl. One or more of the hydrogen atoms of each ofthese groups may be substituted by a like number of halogen atoms suchas fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxygroups having 1-4 carbon atoms preferably, such as methoxy and/orethoxy. Of these, hydrogen atom and methyl group are particularlypreferred.

In the compound (I) according to the present invention, Y is a group

wherein B, D, E₁, E₂, W and m have the same meanings as defined above.The group represented by the following formula:

wherein E₁, E₂ and W have the same meanings as defined above is aheterocyclic group derived from piperidine or piperazine, and two orless of the hydrogen atoms on the ring may be substituted by a likenumber of alkyl groups having 1-4-carbon-atoms preferably, such asmethyl and/or ethyl.

When the above group is a heterocyclic group derived from piperidine, mstands for 0 or 1 (with the proviso that m stands for 1 when Wrepresents C═), and B represents a carbonyl group, a sulfonyl group, analkylene group (an alkylene group having 1-4 carbon atoms preferably,with a methylene group being particularly preferred), an alkenylenegroup (an alkenylene group having 2-5 carbon atoms preferably, with a2-propenylene group being particularly preferred), a group -C(OH)R₂- inwhich R₂ is an aryl group having 6-14 carbon atoms, such as phenyl ornaphthyl, in which one or more of the hydrogen atoms may be substituted,a group -CHR₃- in which R₃ is an aryl group having 6-14 carbon atoms,such as phenyl or naphthyl, in which one or more of the hydrogen atomsmay be substituted, a group

in which the double bond is coupled with W, R₄ represents an aryl grouphaving 6-14 carbon atoms, such as phenyl or naphthyl, or an aralkylgroup having 7-22 carbon atoms, such as benzyl or phenethyl, and thesegroups may be in substituted forms, or a cyclic or acyclic acetal groupin which one or more of the hydrogen atoms may be substituted.

Exemplary cyclic or acyclic acetal groups include:

In the above-described definition of B, preferred examples ofsubstituents on the groups R₂, R₃ and R₄ can include one or more alkylgroups having 1-4 carbon atoms, such as methyl and ethyl; aryl groupshaving 6-14 carbon atoms, such as phenyl and naphthyl; halogen atomssuch as fluorine atoms, chlorine atoms and bromine atoms; alkoxy groupshaving 1-4 carbon atoms, such as methoxy and ethoxy; hydroxyl groups;cyano groups; and nitro groups.

Further, illustrative of substituents on the cyclic or acyclic acetalare halogen atoms such as fluorine atoms, chlorine atoms, and bromineatoms; alkyl groups having 1-4 carbon atoms, such as methyl and ethyl;aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl;aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl;and alkylidene groups having 1-4 carbon atoms preferably, such asmethylidene and ethylidene.

As a particularly preferred example of B, a carbonyl group can bementioned.

When the heterocyclic group is a group derived from piperazine, m standsfor 0 or 1 (preferably 0), and B represents a carbonyl group, a sulfonylgroup, an alkylene group (preferably, an alkylene group having 1-4carbon atoms, with a methylene group being particularly preferred), analkenylene group (preferably, an alkenylene group having 3-6 carbonatoms, with a 2-propenylene group being particularly preferred), a group-CHR₅- in which R₅ represents an aryl group having 6-14 carbon atoms,such as phenyl or naphthyl.

The above-described R₅ may be substituted further, for example, by oneor more of halogen atoms such as fluorine, chlorine and/or bromine,alkyl groups having 1-4 carbon atoms preferably, such as methyl and/orethyl, alkoxy groups having 1-4 carbon atoms preferably, such as methoxyand/or ethoxy, hydroxyl groups, and/or the like.

As a preferred example of the above-described B, a substituted orunsubstituted phenylmethylene group can be mentioned.

Preferred examples of group D can include aromatic hydrocarbon groupshaving 6-28 carbon atoms preferably, such as a phenyl group in which oneor more of the hydrogen atoms may be substituted and a naphthyl group inwhich one or more of the hydrogen atoms may be substituted.

Other preferred examples of D can include aromatic heterocyclic groups,preferably those each of which is monocyclic or bicyclic and containsthree or less hetero atoms, such as pyridyl, pyrimidinyl,benzisothiazolyl, benzisoxazolyl, indazolyl and indolyl groups in whichone or more of hydrogen atoms may be substituted. Examples of the heteroatoms can include oxygen, sulfur and nitrogen atoms.

Examples of the substituents for the above aromatic hydrocarbon group oraromatic heterocyclic group can include halogen atoms such as fluorine,chlorine and bromine; alkyl groups having 1-4 carbon atoms preferably,such as methyl and ethyl; alkoxyl groups having 1-4 carbon atomspreferably, such as methoxy and ethoxy; aryl groups having 6-14 carbonatoms, such as phenyl and naphthyl; aralkyl groups having 7-22 carbonatoms, such as benzyl and phenethyl; aralkyloxy groups having 7-22carbon atoms preferably, such as benzyloxy; cyano groups; nitro groups;carboxyl groups; alkoxycarbonyl groups (with an alcohol moiety thereofhaving 1-6 carbon atoms preferably); lower alkylsulfonylamino groups(with an alkyl moiety thereof having 1-4 carbon atoms preferably);carbamoyl groups; and hydroxyl groups.

Among these examples of group D, preferred ones can include phenylgroups which may be unsubstituted or substituted by one or more ofhalogen atoms, alkoxy groups and/or hydroxyl groups; benzisothiazolylgroups which may be unsubstituted or substituted by one or more halogenatoms; benzisoxazolyl groups which may be unsubstituted or substitutedby one or more halogen atoms; and indazolyl groups which may beunsubstituted or substituted by one or more halogen atoms. Particularlypreferred are an unsubstituted phenyl group; and phenyl groupssubstituted by one or more of fluorine atoms, methoxy groups and/orhydroxyl groups.

Many of the compounds (I) according to the present invention haveisomers. It is to be noted that these isomers and mixtures thereof areall embraced by the present invention.

The pyrrolesulfonamide derivatives (I) according to the presentinvention can be prepared by various processes. It is however preferredto prepare each of them, for example, by using a pyrrolesulfonamidederivative (IIa) or (IIa’), which is available by Process 1 to bedescribed below, and following any one of the processes to be describedas Process 2 onwards.

Process 1:

Pyrrolesulfonamide derivatives (IIa) and (IIa’) useful as startingmaterials can be synthesized, for example, by the following process:

Process (a)

Compounds represented by the formula (IIa) and (IIa’) can be obtained inaccordance with the following reaction scheme, namely, by converting a1-substituted pyrrole-3-sulfonic acid represented by the formula (XII)or a salt thereof into a 1-substituted pyrrole-3-sulfonyl haliderepresented by the formula (XIII), reacting glycine, β-alanine or aderivative thereof represented by the formula (XIV) or an organic orinorganic acid salt thereof with the compound (XIII) and, if necessary,conducting deprotection to obtain a compound represented by the formula(XV) and then subjecting the thus-obtained compound to a ring-closingreaction.

wherein M represents a hydrogen ion, an alkali metal ion, an alkalineearth metal ion or a quaternary ammonium ion, p stands for 1 when Mrepresents a hydrogen ion, an alkali metal ion or a quaternary ammoniumion or p stands for 2 when M represents an alkaline earth metal ion, qstands for 0 or 1, R₆ represents a hydrogen atom or acarboxyl-protecting group, X” represents a chlorine atom or a bromineatom, and R and l have the same meanings as defined above.

Illustrative of M in the compound represented by the formula (XII) inthe above scheme are hydrogen ion; alkali metal ions such as sodium ionand potassium ion; alkaline earth metal ions such as barium ion; andquaternary ammonium ions such as pyridinium ion. As representativepreparation processes of the compound represented by the formula (XII),the following two processes can be mentioned.

[Preparation Process of the Compound (XII)-1]

The compound represented by the formula (XII) can be obtained inaccordance with the following formula, namely, by causing a sulfonatingagent such as sulfur trioxide-pyridine complex to act on a 1-substitutedpyrrole (XVIII) and, if necessary, treating the resultant compound withan acid such as hydrochloric acid or sulfuric acid or a base such assodium hydroxide, sodium carbonate, sodium hydrogencarbonate or bariumhydroxide.

wherein M, R, p and q have the same meanings as defined above.

[Preparation Process of the Compound (XII)-2]

The compound represented by the formula (XII) can be obtained inaccordance with the following formula, namely, by causing trimethylsilylchlorosulfonate (XIX) to act on a1-substituted-2-tri-n-butylstannylpyrrole represented by the formula(XVII) in a solvent, which does not take part in the reaction, such ascarbon tetrachloride or 1,2-dichloroethane and then hydrolyzing theresultant compound. Here, a basic substance may be allowed to existconcurrently, whereby the reaction product can be obtained as a salt.

wherein M, R, p and q have the same meanings as defined above.

Further, the compound (XIII) can be obtained by causing phosphoruspentachloride or phosphorus pentabromide to act on the compound (XII) ina solvent which does not take part in the reaction, such as ethyl etheror toluene.

In addition, as the carboxyl-protecting group represented by the groupR₆ in the compound (XIV), it is possible to use, in addition to loweralkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and t-butyl and aralkyl groups having 7-20 carbon atoms, suchas benzyl and 9-anthrylmethyl, conventional protecting groups such asthose described in T. W. Greene: “Protective Groups in OrganicSynthesis” (John Wiley & Sons, Inc.) and the like.

Further, as an illustrative synthesis process of the compound (XV), aprocess can be mentioned in which a base is added to the compound(XIII), as needed, and glycine, β-alanine or a derivative thereof or anorganic or inorganic acid salt thereof is caused to act. Usable examplesof the base can include organic bases such as triethylamine andpyridine, and inorganic bases such as sodium hydrogencarbonate,potassium carbonate and sodium hydroxide.

The compound (XV) so obtained is subjected to a cyclizing reaction,optionally after removing the protecting group by virtue of a suitablemethod such as the action of an acid or a base, or catalytic reduction.This cyclizing reaction is conducted by treating the compound (XV)together with an organic acid such as methanesulfonic acid, an inorganicacid such as sulfuric acid or polyphosphoric acid or a mixture of suchan organic or inorganic acid and phosphorus pentoxide at roomtemperature to 170°C., preferably at 80-120°C.

In this case, a solvent which does not take part in the reaction may beadded as needed.

Further, the cyclizing reaction can also be practiced by, optionallyafter addition of a catalyst such as dimethylformamide to the compound(XV) in which R₆ is a hydrogen atom, treating the compound with oxalylchloride, thionyl chloride, thionyl bromide, oxalyl bromide, phosgene,phosphorus trichloride, phosphorus tribromide, phosphoryl chloride,phosphoryl bromide or the like to convert it into its corresponding acidhalide and then treating the acid halide at -20°C. to reflux temperaturein the presence of a Lewis acid such as aluminum chloride, aluminumbromide, boron trifluoride-ether complex or tin tetrachloride in asolvent such as dichloromethane, 1,2-dichloroethane or nitromethane. Inthe above-described reactions, the compound (IIa) and the compound(IIa’) can be formed at varied ratios by changing the reactionconditions.

Process (b)

Compounds represented by the formula (IIb) and (IIb’) can be obtained inaccordance with the following reaction scheme, namely, by converting apyrrole-3-sulfonic acid represented by the formula (XX) or a saltthereof into a pyrrole-3-sulfonyl halide represented by the formula(XXI), reacting glycine, β-alanine or a derivative thereof representedby the formula (XIV) or an organic or inorganic acid salt thereof withthe compound (XXI) and, if necessary, conducting deprotection to obtaina compound represented by the formula (XXII) and then subjecting thethus-obtained compound to a ring-closing reaction. The compound (IIa)and compound (IIa’) can then be obtained by introducing groups R to thepyrrole-nitrogen atoms of the compounds (IIb), (IIb’), respectively.

wherein X”’ represents an eliminative group, and M, R, R₆, X”, l and phave the same meanings as defined above.

In the above scheme, the compound represented by the formula (XX) can besynthesized from pyrrole as a starting material by following thepreparation process of the compound (XII)-1 under Process (a) ofProcess 1. Further, the conversion of the compound (XX) into thecompound (IIb) and the compound (IIb’) can be effected in a similarmanner as in the conversion of the compound (XII) into the compound(IIa) and the compound (IIa’) in Process (a) of Process 1.

The conversion from the compound (IIb) into the compound (IIa) can beeffected by treating the compound (IIb) with an organic or inorganicbase and then reacting the compound represented by the formula (XVIa) or(XVIb), or by causing the compound (XVIa) or the compound (XVIb) to acton the compound (IIb) in the presence of such a base.

Examples of the eliminative group represented by the group X”’ in thecompound (XVIa) can include halogen atoms such as chlorine, bromine andiodine, alkylsulfonyloxy groups such as methanesulfonyloxy, andarylsulfonyloxy groups such as p-toluenesulfonyloxy. Exemplary organicor inorganic bases can include potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, sodium hydride, triethylamine,sodium methoxide, and potassium t-butoxide. Further, illustrativesolvents usable in the above reaction include acetone, 2-butanone,acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, anddimethylsulfoxide. The reaction is conducted at -20°C to refluxtemperature.

On the other hand, the conversion from the compound (IIb’) into thecompound (IIa’) can also be effected under the same conditions as in theabove-described conversion from the compound (IIb) into the compound(IIa).

Process 2:

Among the pyrrolesulfonamide derivatives (I), compounds (Ia) in each ofwhich Z₁ and Z₂ are combined together to represent an oxygen atom can besynthesized, for example, by any one of the following processes.

Process (a)

Each compound (Ia) can be obtained in accordance with the followingreaction scheme, namely, by reacting a compound represented by theformula (II) with a compound represented by the formula (III) to convertthe compound (II) into a compound represented by the formula (IV) andthen reacting a nitrogen-containing compound represented by the formula(V) or a salt thereof with the compound (IV).

wherein X and X’ represent the same or different eliminative groups, andA, the ring P, Y and l have the same meanings as defined above.

In the above-described reaction, the conversion from the compound (II)into the compound (IV) can be effected by treating the compound (II)with an organic or inorganic base and then reacting the compound (III)with the compound (II), or by causing the compound (III) to act on thecompound (II) in the presence of such a base.

The groups X and X’ in the compound (III) are eliminative groups.Illustrative can be halogen atoms such as chlorine and bromine,alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxygroups such as p-toluenesulfonyloxy.

Exemplary inorganic bases or organic bases can include sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, sodiumhydride, triethylamine, sodium ethoxide, sodiumbis(trimethylsilyl)amide, and potassium t-butoxide. The reaction can beconducted at -78°C to reflux temperature in a solvent which does nottake part in the reaction.

To prepare the compound (Ia) from the thus-obtained compound (IV) andthe nitrogen-containing compound (V), it is only necessary to react thenitrogen-containing compound (V) or an organic acid salt or inorganicacid salt thereof with the compound (IV), optionally together with anorganic base such as triethylamine, pyridine, collidine or potassiumt-butoxide or an inorganic base such as potassium carbonate, sodiumcarbonate, sodium hydrogencarbonate, sodium hydroxide or sodium hydrideand optionally with the addition of an alkali iodide such as potassiumiodide or sodium iodide, in a solventless manner or in a solvent such asacetone, 2-butanone, acetonitrile, dimethylformamide, methanol, ethanolor the like at room temperature to 150°C.

Examples of the nitrogen-containing compound (V) can include1-phenylpiperazine, 1-(2-fluorophenyl)-piperazine,1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine,1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine,1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine,1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine,1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine,1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine,1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine,1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine,1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine,1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine,1-(2-furoyl)piperazine, 1-(1,2-benzisoxazol-3-yl)piperazine,4-phenylpiperidine, 4-benzylpiperidine,α,α-bis(4-fluorophenyl)-4-piperidinemethanol,4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine,4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine,4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine,4-(6-fluoro-1H-indazol-3-yl-)piperidine,4-[(4-fluorophenyl)sulfonyl]piperidine,4-[bis(4-fluorophenyl)methylene]piperidine, and4-(4-fluorobenzoyl)piperidine ethylene acetal.

These compounds are either known in the art or readily available byprocesses known per se in the art or by processes similar to such knownprocesses.

Process (b)

Further, the compound (Ia) can also be obtained by causing anitrogen-containing compound represented by the formula (VI) to act onthe compound represented by the formula (II) in accordance with thefollowing reaction formula:

wherein A, the ring P, X, Y and l have the same meanings as definedabove.

The conversion from the compound (II) into the compound (Ia) isconducted by causing the compound (VI) to act either after treatment ofthe compound (II) with an inorganic base or an organic base or in thepresence of an inorganic base or an organic base. Reaction conditionsare similar to those employed upon conversion from the compound (II)into the compound (IV) and described above under Process (a) of Process2. Further, the compound (VI) can be synthesized by reacting thecompound (III) with the compound (V) in a manner known per se in theart.

Process 3:

Among the pyrrolesulfonamide derivatives (I), the compounds (Ic) and(Ie) in each of which Z₁ and Z₂ are combined together to represent agroup NOR₁ can each be synthesized by any one of the followingprocesses.

Process (a)

Each compound (Ie) is obtained in accordance with the following reactionscheme, namely, by causing hydroxylamine or a derivative thereof (VII)or a salt thereof to act on a compound represented by the formula (IV)and then causing a nitrogen-containing compound (V) to act.

wherein A, the ring P, R₁, X, Y and l have the same meanings as definedabove.

The reaction between the compound (IV) and the hydroxylamine or itsderivative (VII) is effected, if necessary, in the presence of anorganic base such as pyridine, triethylamine, collidine or sodiumacetate or an inorganic base such as potassium carbonate or sodiumhydroxide. The hydroxylamine or its derivative (VII) may also be used inthe form of an organic acid salt or an inorganic acid salt.

The reaction is conducted at 0°C. to reflux temperature, preferably0°C-100 C by using a suitable solvent, for example, methanol, ethanol,propanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide asneeded.

Further, the conversion from the thus-obtained compound (VIII) into thecompound (Ie) can be effected under similar conditions as in theconversion from the compound (IV) into the compound (Ia) shown aboveunder Process (a) of Process 2.

Process (b)

Each compound (Ic) is obtained by causing hydroxylamine or itsderivative (VII) or a salt thereof to act on a compound (Ib) inaccordance with the following reaction formula.

wherein A, the ring P, R₁ and l have the same meanings as defined above,and Y’ represents a group

in which when W represents CH, B’ represents a sulfonyl group, analkylene group, an alkenylene group, a group -C(OH)R₂- in which R₂represents a substituted or unsubstituted aryl group, a group -CHR₃- inwhich R₃ represents a substituted or unsubstituted aryl group, or asubstituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, B’ represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, B’represents a carbonyl group, a sulfonyl group, an alkylene group, analkenylene group or a group -CHR₅- in which R₅ represents a substitutedor unsubstituted aryl group; and D, E₁, E₂ and m have the same meaningsas defined above.

The conversion from the compound (Ib) into the compound (Ic) can beeffected under similar conditions as the conversion from the compound(IV) into the compound (VIII) shown above under Process (a) of Process3.

Process 4:

Among the pyrrolesulfonamide derivatives (I), the compounds (Id) and(If) in each of which Z₁ represents a hydrogen atom and Z₂ represents ahydroxyl group can each be synthesized by any one of the followingprocesses.

Process (a)

Each compound (If) is obtained in accordance with the following reactionscheme, namely, by reducing a compound represented by the formula (IV)and then causing a nitrogen-containing compound (V) to act.

wherein A, the ring P, X, Y and l have the same meanings as definedabove.

The conversion from the compound (IV) into the compound (IX) isconducted by treating the compound represented by the formula (IV) witha reducing agent such as sodium borohydride, potassium borohydride orsodium cyanoborohydride at -78 C. to reflux temperature, preferably-20°C. to room temperature in a conventionally used solvent.

The conversion from the compound (IX) into the compound (If) can beeffected under similar conditions as the conversion from the compound(IV) into the compound (Ia) shown above under Process (a) of Process 2.

Process (b)

Each compound (Id) is obtained by reducing a compound represented by theformula (Ib) in accordance with the following reaction formula.

wherein A, the ring P, Y’ and l have the same meanings as defined above.

The conversion from the compound (Ib) into the compound (Id) can beeffected under similar conditions as in the conversion from the compound(IV) into the compound (IX) shown above under Process (a) of Process 4.

Process 5:

Among the pyrrolesulfonamide derivatives (I), the compounds (Ig) in eachof which the bond indicated by the dashed line is present and Z₁represents a hydrogen atom can be synthesized by any one of thefollowing processes.

Process (a)

Each compound (Ig) is obtained in accordance with the following reactionscheme, namely, by subjecting a compound represented by the formula (IX)to a dehydration reaction to obtain a compound represented by theformula (X) and then causing a nitrogen-containing compound (V) to acton the compound (X).

wherein A, the ring P, X, Y and l have the same meanings as definedabove.

In the above-described reaction, the conversion from the compound (IX)into the compound (X) can be effected by treating the compound (IX) withan acid such as hydrogen chloride, hydrogen bromide, sulfuric acid,methanesulfonic acid or p-toluenesulfonic acid at -20 C. to 100 C.,preferably at -20 C. to room temperature in a solvent such as water,methanol, ethanol, ethyl acetate, chloroform or toluene.

As an alternative, the conversion into the compound (X) can also beeffected by causing methanesulfonyl chloride, p-toluenesulfonylchloride, phosphorus trichloride, phosphorus oxychloride, thionylchloride or the like and a base such as triethylamine, pyridine orcollidine to act on the compound (IX), if necessary, in a solvent suchas dichloromethane, chloroform or toluene.

The conversion from the compound (X) into the compound (Ig) can beeffected under similar conditions as in the conversion from the compound(IV) into the compound (Ia) described above under Process (a) of Process2.

Process (b)

Each compound (Ig) is obtained by subjecting a compound represented bythe formula (If) to a dehydration reaction in accordance with thefollowing reaction formula:

wherein A, the ring P, Y and l have the same meanings as defined above.

In the above-described reaction, the conversion from the compound (If)into the compound (Ig) can be effected under similar conditions as inthe conversion from the compound (IX) into the compound (X) describedabove under Process (a) of Process 5.

If necessary, the compounds (I) of the present invention obtainedaccording to the above-described processes can each be reacted with oneof various acids to convert the compound into its salt. Then, theresulting salt can be purified by a method such as recrystallization orcolumn chromatography.

Exemplary acids usable for the conversion of the pyrrolesulfonamidederivatives (I) into their salts can include inorganic acids such ashydrochloric acid, nitric acid, sulfuric acid, phosphoric acid andhydrobromic acid; and organic acids such as maleic acid, fumaric acid,tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonicacid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannicacid.

Further, the compounds (I) according to the present invention includethose containing asymmetric centers. Each racemic mixture can beisolated by one or more of various methods, whereby a singleoptically-active substance can be obtained. Usable methods include, forexample:

(1) Isolation by an optically active column.

(2) Isolation by recrystallization subsequent to conversion into a saltwith an optically active acid.

(3) Isolation by an enzyme reaction.

(4) Isolation by a combination of the above methods (1) to (3).

The pyrrolesulfonamide derivatives (I) and their salts, which areobtained as described above, have strong serotonin-2 blocking action aswill be demonstrated in tests to be described subsequently herein.Moreover, the compounds (I) according to the present invention have alsobeen found to include those also having α₁ blocking action. From theresults of toxicity tests, the compounds (I) according to the presentinvention have also been found to possess high safety.

The compounds (I) according to the present invention can therefore beused as pharmaceuticals for the treatment of circulatory diseases suchas ischemic heart diseases, cerebrovascular disturbances, peripheralcirculatory disturbances and hypertension.

When the pyrrolesulfonamide derivatives (I) according to this inventionare used as pharmaceuticals, they can be administered in an effectivedose as they are. As an alternative, they can also be formulated intovarious preparation forms by known methods and then administered.

Exemplary preparation forms as medicines include orally administrablepreparation forms such as tablets, powders, granules, capsules andsyrups as well as parenterally administrable preparation forms such asinjections and suppositories. Whichever preparation form is used, aknown liquid or solid extender or carrier usable for the formulation ofthe preparation form can be employed.

Examples of such extender or carrier include polyvinylpyrrolidone,arabic gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesiumstearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose,crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil,carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin,mannitol, syrup, and the like.

When the compounds (I) according to the present invention are used aspharmaceuticals, their dose varies depending on the administrationpurpose, the age, body weight, conditions, etc. of the patient to beadministered. In oral administration, the daily dose may generally beabout 0.01-1,000 mg.

The present invention will next be described in further detail by thefollowing referential examples, examples and tests. It is however to benoted that the present invention is by no means limited to the followingexamples.

REFERENTIAL EXAMPLE 1

Synthesis of sodium 3-pyrrolesulfonate (Compound 1)

A mixture consisting of 30.0 g (447 mmol) of pyrrole, 75.0 g (471 mmol)of sulfur trioxide-pyridine complex and 250 ml of 1,2-dichloroethane wasrefluxed for 16 hours. The top layer of the reaction mixture was removedby decantation. To the residue, 150 ml of water and 30 g of sodiumcarbonate were added successively. After the resulting mixture wasboiled, the solvent was distilled off under reduced pressure.Ethanol-water (9:1 v/v, 500 ml) was added to the residue, followed byreflux for 1 hour. The reaction mixture was subjected to hot filtration,and the filtrate was allowed to cool down. Precipitated crystals werecollected, washed with chilled ethanol and diethyl ether, and then driedunder reduced pressure, whereby 17.0 g of powdery crystals wereobtained.

REFERENTIAL EXAMPLE 2

Synthesis of Benzyl 2-(3-pyrrolesulfonamide)acetate (Compound 2)

A suspension of 16.9 g (100 mmol) of Compound 1 and 22.9 g (110 mmol) ofphosphorus pentachloride in 750 ml of diethyl ether was stirred at roomtemperature for 2 hours, and was then refluxed for 4 hours. After thereaction mixture was allowed to cool down, it was filtered. The filtratewas washed successively with ice water (twice), a chilled, saturatedaqueous solution of sodium hydrogencarbonate, ice water and a chilled,saturated aqueous solution of sodium chloride. The organic layer wasdried over anhydrous sodium sulfate and then concentrated under reducedpressure, whereby 11.2 g of 3-pyrrolesulfonyl chloride were obtained ascrude crystals.

After a mixture consisting of the whole amount of the thus-obtainedcrude crystals, 32.6 g (96.6 mmol) of glycine benzyl esterp-toluenesulfonate, 19.6 g (193 mmol) of triethylamine and 250 ml oftetrahydrofuran (hereinafter called “THF”) was refluxed for 6 hours, thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue. The resulting mixture was washed successivelywith a 10% aqueous solution of citric acid, water and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The residue wastreated with activated carbon under heat in methanol and thenrecrystallized from methanol, whereby 12.6 g of the title compound wereobtained (yield: 43% based on sodium 3-pyrrolesulfonate).

REFERENTIAL EXAMPLE 3

Synthesis of Benzyl 3-(3-pyrrolesulfonamide)propionate (Compound 3)

A mixture consisting of 1.66 g (10 mmol) of 3-pyrrolesulfonyl chlorideobtained by the process of Referential Example 2, 7.03 g (20 mmol) ofβ-alanine benzyl ester p-toluenesulfonate, 4.05 g (40 mmol) oftriethylamine and 100 ml of THF was refluxed for 16 hours. The reactionmixture was concentrated under reduced pressure, and ethyl acetate wasadded to the residue. The organic layer was washed successively with asaturated aqueous solution of sodium hydrogencarbonate, water, a 10%aqueous solution of citric acid, water and a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (Merck & Co. Inc. No. 9385) (the samesilica gel were used in the subsequent examples) (eluent: ethylacetate/hexane=1/1), whereby 2.82 g of the title compound wereobtained-(yield: 92%).

REFERENTIAL EXAMPLE 4

Synthesis of 2-(3-pyrrolesulfonamide)acetic Acid (Compound 4)

To a solution of 4.85 g (16 mmol) of Compound 2 in 150 ml of THF, 480 mgof 10% palladium on charcoal were added, followed by stirring at roomtemperature for 15 hours under a hydrogen gas stream. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure. The residue was recrystallized from acetonitrile, whereby 2.87g of the title compound were obtained (yield: 88%).

REFERENTIAL EXAMPLE 5

Synthesis of 3-(3-pyrrolesulfonamide)propionic Acid (Compound 5)

To a solution of 19.60 g (64 mmol) of Compound 3 in 400 ml of THF, 1.96g of 5% palladium on charcoal were added, followed by stirring at roomtemperature for 4 hours under a hydrogen gas stream. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure. The residue was recrystallized from ethyl acetate, whereby11.96 g of the title compound were obtained (yield: 86%).

REFERENTIAL EXAMPLE 6

Synthesis of 2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 6) and2,3,4,6-tetrahydropyrrolo[3,4-e][1,2]thiazin-4-one 1,1-dioxide (Compound7)

Under ice cooling, 5.00 g (24.5 mmol) of Compound 4, 4.27 ml (49 mmol)of oxalyl chloride, 120 ml of THF and 3 droplets of DMF were mixed, andthe resulting mixture was stirred for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and 120 ml of 1,2-dichloroethanewere added to the residue. Under ice-cooled stirring, 6.53 g (49 mmol)of aluminum chloride were added, followed by stirring for 2.5 hours atthe same temperature. Under ice cooling, 43 ml of 6 N hydrochloric acidwere added. After the resultant mixture was saturated with sodiumchloride, the thus-obtained mixture was extracted with THF (threetimes). The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was separated bychromatography on a silica gel column (eluent: ethylacetate/hexane=1/1→2/1), whereby 2.27 g of Compound 6 and 62 mg ofCompound 7 were obtained (yields: 50% and 1%, respectively).

REFERENTIAL EXAMPLE 7

Synthesis of 3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 8) and 3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]t-hiazepin-5-one 1,1-dioxide (Compound 9)

A mixture consisting of 6.00 g (27.5 mmol) of Compound 5 and 300 g ofpolyphosphoric acid was stirred for 1 hour over an oil bath of 100 C.The reaction mixture was ice-cooled and was then poured into ice water.A concentrated aqueous solution of sodium hydroxide was added to adjustthe pH to 4. Subsequent to saturation with sodium chloride, theresulting mixture was extracted with THF (3 times). The organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was separated by chromatography on a silica gelcolumn (eluent: ethyl acetate/hexane=2/1), whereby 2.50 g of Compound 8and 497 mg of Compound 9 were obtained (yields: 46% and 9%,respectively).

EXAMPLE 1

Synthesis of Sodium 1-methylpyrrole-3-sulfonate Monohydrate (Compound10)

Under an argon gas atmosphere, a solution of 9.44 g (50 mmol) oftrimethylsilyl chlorosulfonate in 50 ml of carbon tetrachloride wasgradually added under stirring to a solution of 18.5 g (50 mmol) of1-methyl-2-tri-n-butylstannylpyrrole in 150 ml of carbon tetrachloride,followed by stirring at 50 C. for 30 minutes and further at roomtemperature for 30 minutes. To the reaction mixture, 300 ml of asaturated aqueous solution of sodium hydrogencarbonate were added,followed by stirring at room temperature for 20 minutes. The reactionmixture was allowed to separate into two layers. The water layer wascollected and then washed with ethyl ether (100 ml ( 3 times). From thewater layer, water was distilled off under reduced pressure, followed bythe addition of ethanol to the residue. The resulting mixture was boiledand then subjected to hot filtration. The solvent in the filtrate wasdistilled off under reduced pressure, and the thus-obtained solid waswashed with n-pentane (200 ml ( 2 times) and then dried under reducedpressure. Colorless powdery crystals (6.67 g) were obtained.

EXAMPLE 2

Synthesis of sodium 1-methylpyrrole-3-sulfonate monohydrate (Compound10) (Alternative Process)

A mixture consisting of 48.3 g (595 mmol) of 1-methylpyrrole, 100 g (628mmol) of sulfur trioxide-pyridine complex and 325 ml of1,2-dichloroethane was refluxed for 24 hours. The top layer of thereaction mixture was removed by decantation, and 225 ml of water and 100g of sodium carbonate were successively added to the residue. Theresulting mixture was boiled, and the solvent was distilled off underreduced pressure. Ethanol-water (9:1 v/v, 1167 ml) was added to theresidue. The thus-obtained mixture was refluxed for 30 minutes and wasthen subjected to hot filtration. The filtrate was concentrated underreduced pressure and the residue was recrystallized from water-ethanol,whereby 7.05 g of powdery crystals were obtained.

EXAMPLE 3

Synthesis of benzyl 2-[3-(1-methylpyrrole)sulfonamide]propionate(Compound 11)

A suspension of 7.40 g (36.8 mmol) of the sodium1-methylpyrrole-3-sulfonate monohydrate obtained in Example 1 and 9.25 g(44.4 mmol) of phosphorus pentoxide in 303 ml of diethyl ether wasstirred at room temperature for 2 hours. The reaction mixture wasfiltered, and the filtrate was washed successively with chilled water, achilled, half-saturated aqueous solution of sodium hydrogencarbonate,chilled water and a chilled, saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure, whereby 4.14 g of3-(1-methylpyrrole)sulfonyl chloride were obtained as crude crystals.

After a mixture consisting of the whole amount of the thus-obtainedcrude crystals, 12.18 g (34.65 mmol) of β-alanine benzyl esterp-toluenesulfonate, 7.01 g (69.3 mmol) of triethylamine and 200 ml ofTHF was refluxed for 17 hours, the reaction mixture was allowed to cooldown and was then filtered. The filtrate was concentrated under reducedpressure. Ethyl acetate was added to the residue. The resulting mixturewas washed successively with water, a 10% aqueous solution of citricacid, water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: ethyl acetate/hexane=1/1), whereby 5.97 g of the titlecompound were obtained (yield: 50%).

EXAMPLE 4

Synthesis of 3-[3-(1-methylpyrrole)sulfonamide]-propionic Acid (Compound12)

To a solution of 5.595 g (17.36 mmol) of Compound 11 in 200 ml of THF,560 mg of 5% palladium on charcoal were added, followed by stirring atroom temperature for 24 hours under a hydrogen gas stream. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure. The residue was recrystallized from 2-propanol-diisopropylether, whereby 3.49 g of the title compound were obtained (yield: 81%).

EXAMPLE 5

Synthesis of5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin-4-one 1,1-dioxide(Compound 13)

A suspension of 2.06 g (14 mmol) of Compound 6, 1.3 ml (14 mmol) ofdimethyl sulfate, 1.90 g (14 mmol) of potassium carbonate in 140 ml ofacetone was stirred at room temperature for 5 hours. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: THF/methylene chloride=1/7), whereby 2.40 g of the titlecompound were obtained (yield: 86%).

EXAMPLE 6

Synthesis of6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 14)

A suspension of 200 mg (1 mmol) of Compound 8, 126 mg (1 mmol) ofdimethyl sulfate and 138 mg (1 mmol) of potassium carbonate in 20 ml ofacetone was refluxed for 12 hours. The reaction mixture was concentratedunder reduced pressure, followed by the addition of a saturated aqueoussolution of sodium chloride to the residue. The resultant mixture wasextracted with chloroform (3 times). The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column,(eluent: methanol/chloroform=1/19), whereby 135 mg of the title compoundwere obtained (yield: 63%).

EXAMPLE 7

Synthesis of7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 15)

A suspension of 480 mg (2.4 mmol) of Compound 9, 303 mg (2.4 mmol) ofdimethyl sulfate and 332 mg (2.4 mmol) of potassium carbonate in 50 mlof acetone was stirred at room temperature for 22 hours. The reactionmixture was concentrated under reduced pressure, and water and 1 g ofcitric acid were added to the residue. The thus-obtained mixture wasextracted with chloroform (3 times). The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:methanol/chloroform=1/19), whereby 347 mg of the title compound wereobtained (yield: 68%).

EXAMPLE 8

Synthesis of7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 15) (Alternative Process)

A mixture consisting of 497 mg (2 mmol) of Compound 12 and 25 g ofpolyphosphoric acid was stirred for 1 hour over an oil bath of 100°C.The reaction mixture was added to about 200 ml of ice water, andpotassium carbonate was added to adjust the pH to 4. Subsequent tosaturation with sodium chloride, the resultant mixture was extractedwith chloroform (3 times). The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate), whereby 80 mg of the title compound were obtained(yield: 17%).

EXAMPLE 9

Synthesis of 2-(3-chloropropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[-2,3-e][1,2]thiazin-4-one 1,1-dioxide (Compound 16)

A suspension of 200 mg (1 mmol) of Compound 13, 189 mg (1.2 mmol) of1-bromo-3-chloropropane and 345 mg (2.5 mmol) of potassium carbonate in5 ml of acetone was refluxed for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate/methylene chloride=1/30), whereby 125 mg of the titlecompound were obtained (yield: 45%).

EXAMPLE 10

Synthesis of 2-(3-bromopropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[2-,3-e][1,2]thiazin-4-one 1,1-dioxide (Compound 17)

A suspension of 500 mg (2.5 mmol) of Compound 13, 2.5 g (12.5 mmol) of1,3-dibromopropane and 690 mg (5 mmol) of potassium carbonate in 25 mlof acetone was refluxed for 12 hours. The reaction mixture was filtered,and the filtrate was concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column (eluent: ethylacetate/methylene chloride=1/40), whereby 274 mg of the title compoundwere obtained (yield: 34%).

EXAMPLE 11

Synthesis of2-(3-chloropropyl)-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 18)

A suspension of 214 mg (1 mmol) of Compound 14, 630-mg (4-mmol) of1-bromo-3-chloropropane and 276 mg (2 mmol) of potassium carbonate in 5ml of acetone was refluxed for 6 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:ethyl acetate/hexane=1/2), whereby 275 mg of the title compound wereobtained (yield: 95%).

EXAMPLE 12

Synthesis of2-(3-chloropropyl)-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 19)

A suspension of 300 mg (1.08 mmol) of Compound 16, 113 mg (1.62 mmol) ofhydroxylamine hydrochloride and 159 mg (1.62 mmol) of potassium acetatein 10 ml of methanol was refluxed for 7 hours. To the reaction mixture,75 mg (1.08 mmol) of hydroxylamine hydrochloride and 106 mg (1.08 mmol)of potassium acetate were added, followed by further refluxing for 13hours. Post treatment and purification were conducted as in Example 9,whereby 277 mg of the title compound were obtained (yield: 88%).

EXAMPLE 13

Synthesis of2-(3-chloropropyl)-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]-thiazepine-1,1-dioxide(Compound 20)

A suspension of 404 mg (1.39 mmol) of Compound 18, 290 mg (4.17 mmol) ofhydroxylamine hydrochloride and 342 mg (4.17 mmol) of sodium acetate in40 ml of methanol was refluxed for 22 hours. To the reaction mixture, 97mg (1.39 mmol) of hydroxylamine hydrochloride and 114 mg (1.39 mmol) ofsodium acetate were added, followed by further refluxing for 19 hours.The reaction mixture was concentrated under reduced pressure and ahalf-saturated aqueous solution of potassium carbonate was added to theresidue. The thus-obtained mixture was extracted with chloroform (3times). The organic layer was washed successively with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:chloroform), whereby 338 mg of the title compound were obtained (yield:80%).

EXAMPLE 14

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-methyl-1-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin-4-one1,1-dioxide (Compound 21)

A suspension of 54 mg (0.17 mmol) of Compound 17, 46 mg (0.25-mmol) of1-(4-fluorophenyl)piperazine and 57 mg (0.68 mmol) of sodiumhydrogencarbonate in 3.4 ml of dioxane was refluxed for 7 hours. Posttreatment and purification were conducted as in Example 9, whereby 67 mgof the title compound were obtained (yield: 94%).

EXAMPLE 15

Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]propyl]-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 22)

A suspension of 116 mg (0.4 mmol) of Compound 18, 97 mg (0.4 mmol) of4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodiumhydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5 ml ofacetonitrile was refluxed for 17 hours. Post treatment was conducted asin Example 13, and the residue was purified by chromatography on asilica gel column (eluent: methanol/chloroform=3/97), whereby 137 mg ofthe title compound were obtained (yield: 74%).

EXAMPLE 16

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one1,1-dioxide (Compound 23)

A suspension of 116 mg (0.4 mmol) of Compound 18, 108 mg (0.6 mmol) of1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassium carbonateand 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrile wasrefluxed for 19 hours. The reaction mixture was concentrated underreduced pressure, a half-saturated aqueous solution of potassiumcarbonate was added to the residue, and the resultant mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: methanol/chloroform=3/97), whereby 173 mg of the titlecompound were obtained (yield: 100%).

EXAMPLE 17

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one1,1-dioxide (Compound 24)

A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg (1.2 mmol) of1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 304 mg (2.2 mmol) ofpotassium carbonate in 15 ml of 2-butanone was refluxed for 16 hours.The reaction mixture was filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by chromatography on asilica gel column (eluent: ethyl acetate), whereby 276 mg of the titlecompound were obtained (yield: 58%).

EXAMPLE 18

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 25)

A suspension of 116 mg (0.4 mmol) of Compound 19, 108 mg (0.6 mmol) of1-(4-fluorophenyl)piperazine, 134 mg (1.6 mmol) of sodiumhydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml ofacetonitrile was refluxed for 23 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:methanol/methylene chloride=1/20), whereby-152 mg of the title compoundwere obtained (yield: 87%).

EXAMPLE 19

Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-4-hydroxyimino-5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazine1,1-dioxide (Compound 26)

A suspension of 116 mg (0.4 mmol) of Compound 19, 389 mg (0.6 mmol) of4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodiumhydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml ofacetonitrile was refluxed for 24 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (eluent:methanol/methylene chloride=1/15), whereby 90 mg of the title compoundwere obtained (yield: 49%).

EXAMPLE 20

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 27)

A suspension of 112 mg (0.4 mmol) of Compound 20, 108 mg (0.6 mmol) of1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of potassium carbonateand 120 mg (0.8 mmol) of sodium iodide in 6 ml of acetonitrile wasrefluxed for 18 hours. The reaction mixture was concentrated underreduced pressure, and a half-saturated aqueous solution of potassiumcarbonate was added to the residue. The water layer was saturated withsodium chloride, and the thus-obtained mixture was extracted with THF.The organic layer was dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 53 mg of the title compound wereobtained (yield: 29%).

EXAMPLE 21

Synthesis of2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-5-hydroxyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 28)

A suspension of 112 mg (0.4 mmol) of Compound 20, 97 mg (0.4 mmol) of4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodiumhydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 5 ml ofacetonitrile was refluxed for 14 hours. Post treatment and purificationwere conducted as in Example 15, whereby 181 mg of the title compoundwere obtained (yield: 95%).

EXAMPLE 22

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydroxy-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine1,1-dioxide (Compound 29)

To a suspension of 42 mg (0.1 mmol) of Compound 21 in 5 ml of ethanol,38 mg (1 mmol) of sodium borohydride were added gradually underice-cooled stirring. The resulting mixture was stirred under ice coolingfor 1 hour and further at room temperature for 13 hours. Water (5 ml)was added to the reaction mixture. The thus-obtained mixture was stirredat room temperature for 5 hours and then concentrated under reducedpressure. Post treatment and purification were conducted as in Example15, whereby 36 mg of the title compound were obtained (yield: 85%).

EXAMPLE 23

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxy-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine1,1-dioxide (Compound 30)

To a suspension of 240 mg (0.57 mmol) of Compound 23 in 5 ml of ethanol,200 mg (5.3 mmol) of sodium borohydride were added gradually underice-cooled stirring. The resulting mixture was stirred under ice coolingfor 1 hour and further at room temperature for 4 hours. A saturatedaqueous solution of ammonium chloride was added to the reaction mixtureunder ice cooling, followed by the addition of a saturated aqueoussolution of sodium hydrogencarbonate so that the mixture wasalkalinized. The water layer was extracted with methylene chloride. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (eluent: methanol/methylenechloride=1/20), whereby 186 mg of the title compound were obtained(yield: 77%).

EXAMPLE 24

Synthesis of2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydroxy-7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepine1,1-dioxide (Compound 31)

To a suspension of 174 mg (0.4 mmol) of Compound 24 in 8 ml of ethanol,151 mg (4 mmol) of sodium borohydride were added gradually underice-cooled stirring. The resulting mixture was stirred under ice coolingfor 1 hour and further at room temperature for 13 hours. Water (80 ml)was added to the reaction mixture. The thus-obtained mixture was stirredat room temperature for 30 minutes and then concentrated under reducedpressure. Post treatment and purification were conducted as in Example15, whereby 151 mg of the title compound were obtained (yield: 86%).

Physical data of the compounds obtained in Examples 1-24 are shown inTables 1-6. TABLE 1 Comp'd Structural Property NMR (δ ppm)* IR (cm⁻¹⁾No. formula m.p. (recryst'n solvent) ( ): observation frequency ( ):measuring method 10

Colorless powdery crystals ≧250° C. (400Mhz) (D_(2O/TSP-d)_(4**) 3.67 (3H, s), 6.37 (1H, s), 6.75 (1H, s), 7.11 (1H, s)) (KBr)3446, 3132, 1636, 1526, 1186, 1148, 1060, 1048, 942, 802, 699, 662 11

Colorless oil (400Mhz) 2.60 (2H, t, J=6.2Hz), 3.23 (2H, m), 3.66 (3H,s), 4.93 (1H, br. t), 6.38 (1H, m), 6.59 (1H, m), 7.11 (1H, m),7.28-7.41 (5H, m) (film) 3283, 1732, 1519, 1323, 1155, 1119, 801, 699 12

Pale yellow powdery Crystals 95.5-98.0° C. (isopropanol- isopropylether)(400MHz)(DMSO-d_(s/TMS) 2.37 (2H, t, J-7.2Hz), 2.92 (2H, m), 3.66 (3H, s), 6.27 (1H, m), 6.83 (1H, m), 6.99 (1H, br), 7.25 (1H, m), 12.18 (1H, br))(KBr) 3281, 1718, 1522, 1422, 1310, 1241, 1150, 1040, 801, 688*Measured inCDCl_(3 with TMS as an internal standard unless otherwise specifically indicated.)**TSP-d_(4 = sodium 3-(trimethylsilyl)propionate-d) ₄

TABLE 2 Comp'd Structural Property NMR (δ ppm)* IR (cm⁻¹⁾ No. Formulam.p. (recryst'n solvent) ( ): observation frequency ( ): measuringmethod 13

Colorless powdery crystals 142.0-143.0 ° C. (ethyl acetate-hexane)(270MHz) 3.98 (3H, s), 4.16 (2H, d, J=7.3Hz), 5.30 (1H, t, J=7.3Hz) 6.55(1H, d, J=2.6Hz), 6.91 (1H, d, J=2.6Hz) (KBr) 3196, 1673, 1648, 1382,1328, 1307, 1209, 1162, 1142, 1083, 762 14

Colorless prism crystals 132.0-133.5° C. (chloroform) (270MHz)(DMSO-d_(s/TMS) 3.01 (2H, m), 3.33 (2H, m), 3.82 (3H, s), 6.52 (1H, d, J=2.6Hz), 7.22 (1H, d, J=2.6Hz), 7.86 (1H, t, J=5.6Hz))(KBr) 3303, 1652, 1481, 1403, 1321, 1200, 1151, 1094, 1018, 983, 866,783, 766, 674 15

Pale yellow powdery prism crystals 135.0-138.0°0 C. (ethyl acetate-isopropyl ether) (400MHz)(DMSO-d_(s/TMS) 2.83 (2H, m), 3.38 (2H, m), 3.68 (3H, s), 7.43 (1H, d, J=2.4Hz), 7.45 (1H, d, J=2.4Hz), 7.75 (1H, br. s.))(KBr) 3235, 1642, 1538, 1322, 1242, 1153, 1050, 858, 755 16

Colorless prism crystals 96.0-97.0 ° C. (ethyl acetate-hexane) (270Mhz)2.08 (2H, quint., J=6.6Hz), 3.35 (2H, t, J=6.6Hz), 3.65 (2H, t,J=6.6Hz), 3.99 (3H, s), 4.22 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.92 (1H,d, J=2.6Hz) (KBr) 1680, 1387, 1326, 1210, 1150, 1011, 900, 774, 705*Measured inCDCl_(3 with TMS as an internal standard unless otherwise specifically indicated.)

TABLE 3 Comp'd Structural Property NMR (δ ppm)* IR (cm⁻¹⁾ No. Formulam.p. (recryst'n solvent) ( ): observation frequency ( ): measuringmethod 17

Colorless prism crystals 84.0-85.0° C. (ethyl acetate-hexane) (270MHz)2.16 (2H, quint., J=6.6Hz), 3.34 (2H, t, J=6.6Hz), 3.50 (2H, t,J=6.6Hz), 399 (3H, s), 4.23 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.91 (1H, d,J=2.6Hz) (KBr) 1680, 1484, 1389, 1328, 1260, 1212, 1149, 1006, 898, 71518

Colorless needle crystals 71.0-74.0° C. (ethyl acetate-hexane) (270MHz)2.04 (2H, quint., J=6.6Hz), 3.17 (2H, t, J=6.6Hz), 3.25 (2H, m),3.53-3.67 (4H, m), 3.92 (3H, s), 6.66 (1H, d, J=2.6Hz), 6.81 (1H, d,J=2.6Hz) (KBr) 3120, 2964, 1661, 1472, 1405, 1375, 1330, 1213, 1196,1152, 1096, 1026, 964, 854, 757, 707 19

Colorless prism crystals 126.0-127.0° C. (ethyl acetate-hexane) (270MHz)2,09 (2H, quint., J=6.6Hz), 3,17 (2H, t, J=6.6Hz), 3.67 (2H, t,J=6.6Hz), 3.84 (3H, s), 4.64 (2H, s), 6.48 (1H, d, J=2.6Hz), 6.71 (1H,d, J=2.6Hz), 7.53 (1H, s) (KBr) 3465, 1610, 1483, 1365, 1298, 1207,1148, 1023, 994, 936, 848, 795 20

Colorless prism crystals 110.0-111.0° C. (ethyl acetate-hexane) (400MHz)2.04 (2H, quint., J=6.4Hz), 3.15-3.21 (4H, m), 3.60-3.66 (4H, m), 3.73(3H, s), 6.57(1H, d, J=2.9Hz), 6.60 (1H, d, J=2.9Hz), 7.59 (1H, s) (KBr)3358, 3120, 2949, 1486, 1413, 1308, 1194, 1142, 1062, 988, 953, 936,907, 870, 757 730, 707*Measured inCDCl_(3 with TMS as an internal standard unless otherwise specifically indicated.)

TABLE 4 Property Comp'd Structural m.p.(recryst'n NMR (δ ppm)* IR(cm^(−1) ( ):) No. Formula solvent) ( ): observation frequency measuringmethod 21

Colorless needle crystals 141.0-142.0° C. (ethyl acetate-hexane)(270MHz) 1.81 (2H, quint. J=7.3Hz), 2.47 (2H, t, J=7.3Hz), 2.58(4H, m),3.11 (4H, m), 3.27 (2H, t, J=7.3Hz), 3.98 (3H, s), 4.23 (2H, s), 6.52(1H, d, J=2.6Hz), 6.84-6.99 (5H, m) (KBr) 2950, 2833, 1684, 1510, 1386,1335, 1238, 1155, 1005, 900, 815, 782, 719 22

Colorless powdery crystals 105.0-107.0° C. (ethyl acetate-hexane)(270MHz) 1.69-1.89 (6H, m), 2.06 (2H, m), 2.41 (2H, m), 2.95 (2H, m),3.06 (2H, t, J=7.3Hz), 3.18 (1H, m), 3.24 (2H, m), 3.56 (2H, m), 3.92(3H, s), 6.65 (1H, d, J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 7.14 (2H, m),7.96 (2H, m) (KBr) 2948, 2778, 1726, 1668, 1596, 1508, 1464, 1405, 1375,1322, 1228, 1146, 1046, 980, 856, 755 23

Colorless powdery crystals 72.0-73.5° C. (ethyl acetate-hexane) (270MHz)1.77 (2H, quint., J=7.3Hz), 2.44(2H, t, J=7.3Hz), 2.57 (4H, m),3.03-3.14(6H, m), 3.25 (2H, m), 3.56 (2H, m), 3.92 (3H, s), 6.65 (1H, d,J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 6.87 (2H, m), 6.95 (2H, m) (KBr) 3609,3128, 2842, 1661, 1508, 1452, 1404, 1386, 1318, 1247, 1216, 1143, 1038,1014, 980, 958, 930, 846, 828, 780, 710 24

Colorless oil (400MHz) 1.8 (2H, quint., J=7.0Hz), 2.46 (2H, t, J=7.0Hz),2.58 (4H, m), 3.05 (2H, m), 3.10 (4H, m), 3.16 (2H, t, J=7.0Hz), 3.68(2H, m), 3.71 (3H, s), 6.86 (2H, m), 6.95 (2H, m), 7.14 (1H, d,J=2.5Hz), 7.25 (1H, d, J=2.5Hz) (film) 3124, 2945, 2819, 1655, 1531,1509, 1456, 1329, 1232, 1156, 1038, 959, 827, 717*Measured inCDCl_(3 with TMS as an internal standard unless otherwise specifically indicated.)

TABLE 5 Property Comp'd Structural m.p. (recryst'n NMR (δ ppm)* ( ): IR(cm^(−1) ( ):) No. formula solvent) observation frequency measuringmethod 25

Colorless needle crystals 177.0-178.0° C. (ethanol) (270MHz)(DMSO-d_(s/TMS) 1.71 (2H, m), 2.38 (2H, t, J=6.6Hz), 2.47 (4H, m), 2.94 (2H, t, J=6.6Hz), 3.05 (4H, m), 3.83 (3H, s), 4.51 (2H, s), 6.42 (1H, d, J=3.3Hz), 6.93 (2H, m), 7.02 (2H, m), 7.06 (1H, d, J=3.3Hz), 11.89 (1H, s))(KBr) 2833, 1513, 1332, 1244, 1203, 1156, 950, 824, 725 695 26

Colorless needle crystals 209.0-210.0° C. (decomp'd) (ethanol) (270MHz)(DMSO-d_(s/TMS) 1.56 (2H, m), 2.64-2.78 (4H, m), 2.04 (2H, m), 2.33 (2H, m), 2.85-2.95 (4H, m), 3.35 (1H, m), 3.84 (3H, s), 4.49 (2H, s), 6.42 (1H, d, J=3.3Hz), 7.08 (1H, d, J=3.3Hz), 7.34 (2H, m), 8.04 (2H, m), 11.89 (1H, s))(Kbr) 2953, 1684, 1598, 1508, 1412, 1330, 1206, 1157, 973, 942, 837,778, 739, 721 27

Colorless powdery crystals 237.0-239.0° C. (acetonitrile- isopropylether) (400MHz)(DMSO-d_(s/TMS) 1.69 (2H, quint., J=6.9Hz), 2.33 (2H, m), 2.48 (4H, m), 2.93 (2H, m), 2.99 (2H, t, J=6.9Hz), 3.05 (4H, m), 3.55 (2H, m), 3.67 (3H, s), 6.37 (1H, d, J=2.9Hz), 6.89 (1H, d, J=2.9Hz), 6.92 (2H, m), 7.02 (2H, m), 11.78 (1H, s))(KBr) 2960, 2824, 1509, 1448, 1323, 1245, 1231, 1195, 1150, 1040, 993,995, #924, 816, 757 728, 706 28

Colorless powdery crystals 192.5-195.0° C. (ethyl acetate-hexane)(400MHz) 1.72-1.96 (6H, m), 2.14 (2H, m), 2.46 (2H, m), 2.99-3.08 (4H,m), 3.16-3.28 (3H, m), 3.55 (2H, m), 3.75 (3H, s), 6.56(1H, d, J=3.0Hz),6.59 (1H, d, J=3.0Hz), 7.14 (2H, m), 7.95 (2H, m), 10.13 (1H, br. s)(Kbr) 3402, 2953, 1680, 1597, 1505, 1450, 1412, 1327, 1196, 1150, 993,973, 855, 726, 700*Measured inCDCl_(3 with TMS as an internal standard unless otherwise specifically indicated.)

TABLE 6 Property Comp'd Structural m.p. (recryst'n NMR (δ ppm)* IR(cm^(−1) ( ):) No. formula solvent) ( ): observation frequency measuringmethod 29

Colorless powdery crystals 157.5-161.5° C. (ethyl acetate-hexane)(400MHz) 1.83 (2H, m), 2.35 (2H, m), 2.46 (1H, m), 2.61 (2H, m), 2.70(1H, m), 2.82 (2H, m), 2.95-3.05 (3H, m), 3.52 (1H, dd, J=2.0Hz,14.8Hz), 3.63 (3H, s), 3.92 (1H, m), 4.20 (1H, dd, J=2.8Hz, 14.8Hz),4.52 (1H, t, J=2.3Hz), 6.44 (1H, d, J=3.0Hz), 6.60 (1H, d, J=3.0Hz),6.79 (2H, m), 6.94 (2H, m) (KBr) 3528, 2953, 2820, 2360, 1510, 1464,#1310, 1232, 1209, 1140, 1059, 1003, 958, 920, 815, 776, 738, 713 30

Colorless oil (270MHz) 1.82 (2H, quint. J=7.3Hz), 1.93 (1H, m), 2.14(1H, m), 2.40 (1H, m), 2.49-2.65 (5H, m), 2.78 (1H, m), 3.10 (4H, m),2.25-2.38 (2H, m), 3.67 (3H, s), 4.40 (1H, m), 4.92 (1H, m), 6.43-6.45(2H, m), 6.87 (2H, m), 6.95 (2H, m) (film) 3500, 2822, 1731, 1505, 1456,1232, 1138, 930, 818, 706 31

Colorless plate crystals 165.5-169.0° C. (ethyl acetate-hexane) (400MHz)1.81 (2H, quint., J=7.1Hz), 1.92 (2H, m), 2.47 (2H, m), 2.59 (4H, m),2.83 (1H, m), 3.05-4.05 (6H, m), 3.44 (1H, m), 3.62 (3H, s), 4.12 (1H,m), 4.87 (1H, br. s), 6.56 (1H, d, J=2.4Hz), 6.87 (2H, m), 6.95 (2H, m),7.02 (1H, d, J=2.4Hz) (KBr) 3122, 2959, 2828, 1509, 1448, 1328, 1247,1151, 1124, 1062, 1009, 928, #897, 830, 780, 758, 711, 692*Measured inCDCl_(3with TMS as an internal standard unless otherwise specifically indicated.)

Tests

With respect to certain compounds of the present invention, theiranti-serotonin (5-HT) action and anti-α₁ action were investigated by themethods which will be described below. The results of somerepresentative compounds are shown in Table 7.

(1) Anti-Serotonin (5-HT) Action

The superior mesenteric artery of each Hartley male guinea pig (bodyweight: 300-500 g) was excised. A preparation cut in a helical form wassuspended under resting-tension of 0.3 g in a Magnus cylinder filledwith the Tyrode solution which had been aerated with a gas mixture of95% O₂ and 5% CO₂ and maintained at 37°C. Using an isometric transducer(“UL-10”, manufactured by SHINKOH K.K.) and a pressure preamplifier(“DSA-605A”, manufactured by SHINKOH K.K.), variations in tension weremeasured. The isometric tensions were recorded on a pen-writing recorder(“VP-6537A”, manufactured by NATIONAL K.K.). Taking the contractioninduced by 10⁻⁵ M serotonin (5-HT) as 100%, the percent contractions by10⁻⁵ M 5-HT in the presence of each test drug at 10⁻⁷ M and 10⁻⁶ M weredetermined as anti-5-HT action.

(2) Anti-α₁ Action

The thoracic aorta of each Hartley male guinea pig (body weight: 300-500g) was excised. A preparation cut in a helical form was suspended under1 g load in a Magnus cylinder filled with the Tyrode solution which hadbeen aerated with a gas mixture of 95% O₂ and 5% CO₂ and maintained at37 C. Using an isometric transducer (“TB-612J”, manufactured by NihonKohden Corporation) and a pressure preamplifier (“AP-620G”, manufacturedby Nihon Kohden Corporation), variations in tension were measured. Theisometric tensions were recorded on a thermal pen-writing recorder(“WT-647G”, manufactured by Nihon Kohden Corporation). Taking the toniccontraction induced by 10⁻⁵ M norepinephrine (NE) as 100%, the percentcontractions upon addition of each test drug at 10⁻⁸ M and 10⁻⁷ M weredetermined and recorded as α₁ action. TABLE 7 Anti 5-HT action Antiα_(1action) (% of Control) (% of Control Comp'd No. 10^(−7 M) 10^(−6 M)10^(−8 M) 10^(−7 M) 22 75.3 21.3 91.2 64.9 25 69.8 19.6 65.3 24.1 2654.6 18.2 99.6 73.1 27 76.2 22.7 91.2 53.0 30 83.5 37.2 102.3 88.0

Capability of Exploitation in Industry

The pyrrolesulfonamide derivatives (I) and their salts according to thepresent invention have strong serotonin-2 blocking action and have highsafety. Accordingly, the present invention has made it possible toprovide pharmaceuticals making use of antagonistic action againstserotonin-2 receptors, for example, therapeutics for various circulatorydiseases such as ischemic heart diseases, cerebrovascular disturbancesand peripheral circulatory disturbances. Further, the compoundsaccording to the present invention include those also having α₁ blockingaction in combination. Since these compounds are also effective asantihypertensives, they are extremely used for therapeutics for a widevariety of circulatory diseases.

1. A pyrrolesulfonamide derivative or a salt thereof, saidpyrrolesulfonamide derivative being represented by the following formula(I):

wherein the ring p represented by

means a pyrrole ring represented by the following structure:

in which R represents an alkyl group, a cycloalkyl group, acycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group;the dashed line indicates the presence or absence of a bond; and, whenthe bond indicated by the dashed line is present, Z₂ is not present andZ₁ represents a hydrogen atom but, when the bond indicated by the dashedline is absent, Z₁ represents a hydrogen atom and Z₂ represents ahydroxyl group; or Z₁ and Z₂ are combined together to represent anoxygen atom or a group NOR₁ in which R₁ represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group or a substituted or unsubstituted aryl group; l represents0 or 1; A represents a substituted or unsubstituted alkylene group, asubstituted or unsubstituted alkenylene group or a substituted orunsubstituted alkynylene group; and Y represents a group

in which W represents CH, C═ or a nitrogen atom; and, when W representsCH, m stands for 0 or 1, B represents a carbonyl group, a sulfonylgroup, an alkylene group, an alkenylene group, a group -C(OH)R₂- inwhich R₂ represents a substituted or unsubstituted aryl group, a group-CHR₃- in which R₃ represents a substituted or unsubstituted aryl group,or a substituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, m stands for 1, B represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group-or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, m standsfor 0 or 1, and B represents a carbonyl group, a sulfonyl group, analkylene group, an alkenylene group or a group -CHR₅- in which R₅represents a substituted or unsubstituted aryl group; E₁ and E₂ eachindependently represents a hydrogen atom or a lower alkyl group; and Drepresents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted aromatic heterocyclic group.
 2. Apyrrolesulfonamide derivative or a salt thereof according to claim 1,wherein in the formula (I), Z₁ represents a hydrogen atom and Z₂represents a hydroxyl group.
 3. A pyrrolesulfonamide derivative or asalt thereof according to claim 1, wherein in the formula (I), Z₁ and Z₂are combined together to represent an oxygen atom or a group NOH.
 4. Apyrrolesulfonamide derivative or a salt thereof according to claim 1, 2or 3, wherein in the formula (I), A is a trimethylene group.
 5. Apyrrolesulfonamide derivative or a salt thereof according to claim 1, 2,3 or 4, wherein in the formula (I), W represents a nitrogen atom, mstands for 0, and D represents a substituted or unsubstituted phenylgroup.
 6. A pyrrolesulfonamide derivative or a salt thereof according toclaim 1, 2, 3, 4 or 5, wherein in the formula (I), E₁ and E₂ bothrepresent hydrogen atoms.
 7. A pyrrolesulfonamide derivative or a saltthereof according to claim 1, 2, 3, 4, 5 or 6, wherein in the formula(I), the ring P represents the following formula:

wherein R has the same meaning as defined above.
 8. A process for thepreparation of a pyrrolesulfonamide derivative represented by thefollowing formula (Ia):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reacting a compound, which is represented by thefollowing formula (III): X-A-X’ (III) wherein A has the same-meaning asdefined above and X and X’ represent the same or different eliminativegroups, to a compound represented by the following formula (II):

wherein the ring P and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula (IV):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H-Y (V) wherein Y has the same meaning as definedabove.
 9. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ia):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reacting a compound, which is represented by thefollowing formula (VI): X-A-Y (VI) wherein A, X and Y have the samemeanings as defined above, to a compound represented by the followingformula (II):

wherein the ring P and l have the same meanings as defined above.
 10. Aprocess for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Ic):

wherein A, the ring P, R₁ and l have the same meanings as defined above,and Y’ represents a group

in which when W represents CH, B’ represents a sulfonyl group, analkylene group, an alkenylene group, a group -C(OH)R₂- in which R₂represents a substituted or unsubstituted aryl group, a group -CHR₃- inwhich R₃ represents a substituted or unsubstituted aryl group, or asubstituted or unsubstituted cyclic or acyclic acetal group; when Wrepresents C═, B’ represents a group

in which the double bond is coupled with W and R₄ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, B’represents a carbonyl group, a sulfonyl group, an alkylene group, analkenylene group or a group -CHR₅- in which R₅ represents a substitutedor unsubstituted aryl group; and D, E₁, E₂ and m have the same meaningsas defined above, which comprises: reacting a hydroxylamine or aderivative thereof, which is represented by the following formula (VII):NH₂OR₁ (VII) wherein R₁ has the same meaning as defined above, with apyrrolesulfonamide derivative represented by the following formula (Ib):

wherein A, the ring P, Y’ and l have the same meanings as defined above.11. A process for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Id):

wherein A, the ring P, Y’ and l have the same meanings as defined above,which comprises: reducing a pyrrolesulfonamide derivative represented bythe following formula (Ib):

wherein A, the ring P, Y’ and l have the same meanings as defined above.12. A process for the preparation of a pyrrolesulfonamide derivativerepresented by the following formula (Ie):

wherein A, the ring P, R₁, Y and l have the same meanings as definedabove, which comprises: reacting a hydroxylamine or a derivativethereof, which is represented by the following formula (VII): NH₂OR₁(VII) wherein R₁ has the same meaning as defined above, to a compoundrepresented by the following formula (IV):

wherein A, the ring P, X and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula(VIII):

wherein A, the ring P, R₁, X and l have the same meanings as definedabove; and then reacting a nitrogen-containing compound represented bythe following formula (V): H-Y (V) wherein Y has the same meaning asdefined above.
 13. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (If):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: reducing a compound represented by the followingformula (IV):

wherein A, the ring P, X and l have the same meanings as defined above,thereby obtaining a compound represented by the following formula (IX):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H-Y (V) wherein Y has the same meaning as definedabove.
 14. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ig):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: subjecting a compound, which is represented by thefollowing formula (IX):

wherein A, the ring P, X and l have the same meanings as defined above,to dehydration treatment, thereby obtaining a compound represented bythe following formula (X):

wherein A, the ring P, X and l have the same meanings as defined above;and then reacting a nitrogen-containing compound represented by thefollowing formula (V): H-Y (V) wherein Y has the same meaning as definedabove.
 15. A process for the preparation of a pyrrolesulfonamidederivative represented by the following formula (Ig):

wherein A, the ring P, Y and l have the same meanings as defined above,which comprises: subjecting a compound, which is represented by thefollowing formula (If):

wherein A, the ring P, Y and l have the same meanings as defined above,to dehydration treatment.
 16. A compound represented by the followingformula (II):

wherein the ring P and l have the same meanings as defined above.
 17. Acompound represented by the following formula (XI):

wherein the dashed line, A, the ring P, X, Z₁, Z₂ and l have the samemeanings as defined above.
 18. A process for the preparation of apyrrolesulfonamide derivative represented by the following formula (IIa)or (IIa’):

wherein R and l have the same meanings as defined above, whichcomprises: converting a 1-substituted-pyrrole-3-sulfonic acid or a saltthereof, which is represented by the following formula (XII):

wherein M represents a hydrogen ion, an alkali metal ion, an alkalineearth metal ion or a quaternary ammonium ion, p stands for 1 when Mrepresents a hydrogen ion, an alkali metal ion or a quaternary ammoniumion or p stands for 2 when M represents an alkaline earth metal ion, qstands for 0 or 1, and R has the same meaning as defined above, into acompound represented by the following formula (XIII):

wherein X” represents a chlorine atom or a bromine atom; causing glycineor β-alanine or a derivative thereof, which is represented by thefollowing formula (XIV): NH₂(CH₂)lCH₂COOR₆ (XIV) wherein R₆ represents ahydrogen atom or a carboxyl-protecting group, to act, thereby obtaininga compound represented by the following formula (XV):

wherein R, R₆ and l have the same meanings as defined above; and thensubjecting said compound to ring closure.
 19. A process for thepreparation of a pyrrolesulfonamide derivative represented by thefollowing formula (IIa) or (IIa’):

wherein R and l have the same meanings as defined above, whichcomprises: reacting a compound, which is represented by the formula(XVIa) or (XVIb): R-X”’ (XVIa) (RO)₂SO₂ (XVIb) wherein X”’ represents aneliminative group and R has the same meaning as defined above, with acompound represented by the following formula (IIb) or (IIb’):

wherein l has the same meaning as defined above.
 20. A compoundrepresented by the following formula (XV):

wherein R, R⁶ and l have the same meanings as defined above.
 21. Acompound represented by the following formula (XII):

wherein M, R, p and q have the same meanings as defined above.
 22. Acompound according to claim 21, wherein in the formula (XII), R is amethyl group, M is a sodium ion, p is 1, and q is 0 or
 1. 23. A processfor the preparation of a 1-substituted-pyrrole-3-sulfonic acid or a saltthereof, which comprises treating a 1-substituted-pyrrole with sulfurtrioxide-pyridine complex.
 24. A process for the preparation of acompound represented by the following formula (XII):

wherein M, R, p and q have the same meanings as defined above, whichcomprises treating a compound, which is represented by the followingformula (XVII):

wherein R has the same meaning as defined above, with trimethylsilylchlorosulfonate, followed by alkali hydrolysis.
 25. A pharmaceuticalcomprising, as an effective ingredient, a pyrrolesulfonamide derivativeor a salt thereof according to claim
 1. 26. A therapeutic forcirculatory diseases, comprising as an effective ingredient apyrrolesulfonamide derivative or a salt thereof according to claim 1.27. A serotonin-2 receptor antagonist, comprising as an effectiveingredient a pyrrolesulfonamide derivative or a salt thereof accordingto claim 1.